This research proposal is concerned with our earlier findings that either morphine or codeine administered intraventricularly to pentobarbital-anesthetized rabbits and/or rats exerted an analeptic effect which was potentiated by naloxone or naltrexone pretreatment. Codeine, but not morphine, also exerted its analeptic effect when given intravenously, even without prior treatment with an opiate antagonist. The analeptic effect was abolished by atropine pretreatment, suggesting involvement of a cholinergic mechanism. We propose to fully characterize the dose-response, time-effect and phramacological profile of this opiate arousal effect in the rat, and then proceed to determine by stereotaxic microinjection techniques their sites(s) of action in the brain. Upon establishing these properties we plan to determine whether other opiates of different analgesic potencies and chemical structures possess analeptic activity. They will be ranked according to their analeptic potencies, and possible correlations made between this property and any of their other known actions. Similar studies will be carried out with the various endogenous opioids and opiate antagonists. We shall then attempt to establish whether specific opiate receptor subtypes are involved in this action. Because the data thus far suggest possible relationships between opiate-induced arousal and cholinergic mechanisms, we plan to focus much of our neuroanatomical and neurochemical studies on central cholinergic pathways. Central cholinergic activity will be assessed by measuring high affinity choline uptake into synaptosomes from various regions of the brain, and levels of ACh and choline will be monitored. The main objective of this proposal is to understand the nature of this previously unknown property of the opiates and to determine whether it contributes to the overall pharmacology of those agents. Recent reports suggest that the arousal property of codeine may be useful in the treatment of narcolepsy, while that same property of morphine in chronic pain management may lead to sleep disorders. These studies may help establish the pharmacological bases of such clinical observations.